Process for making siponimod and intermediate thereof
a technology of siponimod and siponimod, which is applied in the preparation of oximes, halogenated hydrocarbon preparations, and sulfonic acid esters, etc., can solve the problems of reducing the yield of the process
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example 1
on of 4-(bromomethyl)-1-cyclohexyl-2-(trifluoromethyl)benzene
[0102]
[0103]3.2 g of (4-cyclohexyl-3-(trifluoromethyl)phenyl)methanol was mixed with 22 ml of toluene. To the solution 12.8 ml of Hydrobromic acid (33% sol. in AcOH) was added at 20° C.-25° C. dropwise in course of 10 minutes with stirring. Then, 1.3 ml of Acetic anhydride was added with stirring at 20° C.-25° C. The resulting mixture was stirred at 20° C.-25° C. for 21 hours. The mixture was cooled to 0-2° C. and 30 ml of water was slowly added while the temperature of the mixture was kept below 20° C. 60 ml of n-heptane was added and the mixture was allowed to warm to 20° C.-25° C. The phases were separated and the organic phase was washed consecutively with 30 ml of water, 30 ml of saturated aqueous NaHCO3 and 30 ml of water. The organic phase was mixed with 0.6 g of silica gel. The suspension was agitated for 20 minutes. The suspension was filtered and the filtrate was concentrated (40-50° C., 80 -->40 mbar, then 5-10°...
example 2
ethyl-4-(hydroxymethyl)phenyl)ethan-1-one oxime
[0104]
[0105]15 g of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one was dissolved in 150 ml of methanol. The solution was cooled to 0-5° C. and 8.3 g sodium acetate followed by 7 g of hydroxylamine hydrochloride were added. The mixture was stirred at 0-5° C. for 5 minutes, the mixture was warmed to 20° C.-25° C. over approx. 70 minutes. The mixture was stirred for 110 minutes in total. The mixture was diluted with 150 ml of water at 20-25° C. and stirred for 20 minutes. Another 50 ml of water was added and the mixture was cooled to 0-2° C. It was stirred at this temperature for 1 hour. The formed solid was collected by filtration, washed with 25 ml of cold water and dried to provide 13.4 g (82% of the theoretical yield) of (E)-1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one oxime as white solid, in 99.75% purity (HPLC in). XRPD of the obtained solid compound corresponds to XRPD pattern depicted in FIG. 1.
example 3
ethyl-4-(hydroxymethyl)phenyl)ethan-1-one oxime
[0106]
[0107]15 g of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one was dissolved in 150 ml of methanol and 8.3 g sodium acetate followed by 7 g of hydroxylamine hydrochloride were added. The resulting mixture was stirred at 20° C.-25° C. for 60 minutes. The mixture was concentrated to the amount approx. 60 g. 150 ml of saturated aqueous NaHCO3 and 90 ml of ethyl acetate were added, the phases were separated and the aqueous phase was extracted twice with 90 ml of ethyl acetate. The combined organic phases were washed with 90 ml of water. The organic phase was dried using MgSO4, filtered and the filtrate was concentrated to approx. ½ of the original volume. It was diluted with 180 ml of toluene. The mixture was concentrated to the amount approximately 90 g. The suspension was stirred overnight at 20° C.-25° C. The mixture was filtrated and the obtained solid was dried to provide 14.11 g (86% of the theoretical yield) of (E)-1-(3-ethyl-4-(...
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